Introduction

Throughout human history there have been periods when what was considered mere whimsy, the fruit of a fantastic imagination, becomes real. These situations challenge and change our ideas of what is considered normal and moral. The emerging concept of xenotransplantation presents challenges, but also opportunities to potentially cure many diseases that otherwise have no treatments or limited treatments.

Xenotransplantation is the transfer of an organ, tissue, or cells from one species to a different species.

Xenotransplantation is the transplantation of an organ or tissue from one species to a different species, and here xenotransplantation refers to the transplantation from a non-human species into a human being. It is curious to consider that in the earliest tales of many cultures we can find the idea of bringing together different animal body parts into one; take for example the Chimera presented in Homer’s The Odyssey. The Chimera is an animal consisting of the head of a lion fused to parts of a goat and a dragon. Currently, medical science is presenting the very real possibility that people could receive organs transplanted from pigs. In this way, we are witnessing the realization of the Chimera in the form of xenotransplantation.

Transplantation of organs became viable in the late 20th century with the advent of immunosuppressant drugs that could curb the human body’s rejection response.

Why xenotransplantation?

During the 20th century medical researchers began to develop the skills and techniques required to graft certain body tissues and, later, whole organs, into human recipients as a way to improve health and preserve life. Though the transplantation of cartilage became relatively successful in the early 20th century, the transplantation of organs presented the obstacle of immune rejection. Thus, it was not until the development of powerful immunosuppressive drugs in the 1970’s and 1980’s to curb this immune attack that transplantation of kidneys, hearts and other organs could become a realistic medical treatment. Today, most major hospitals around the world host transplant clinics with organ donation organized on a national scale. But in the 21st century, with the tremendous success of transplantation, we are faced with a new challenge: in the United States alone, more than 110,000 men, women and children are waiting for organ transplants, a demand that cannot be met with current organ donation rates. Obviously, without a life-saving organ transplant many people who would otherwise benefit from a transplant will die.

From this need comes the dream of having an unlimited supply of tissues and organs for transplantation. One proposed solution is to harvest tissues and organs from animals for transplantation into human patients - a process called “xenotransplantation.”

Xenotransplantation is currently being researched as a potential cure for Type 1 diabetes.

The arrival of xenotransplantation technology ushers in new possibilities and new dilemmas. As with most human innovations, there will be no blanket answer, no moral cover-all, that will help us decide what is acceptable. Rather, we will have to wade through the details and decide on a case by case basis whether to more broadly introduce these innovations into modern society. As part of this process, this article will present a case for the use of xenotransplantation with specific reference to its potential to provide a cure for Type 1 diabetes, a disease for which there is currently no cure. For further information on the history of xenotransplantation, the reader is referred to an excellent review by Dr Jack–Yves Deschamps.1

Type 1 diabetes is a chronic disease in which there are high levels of sugar (glucose) in the blood.

What is Type 1 diabetes?

Type 1 diabetes is a serious disease diagnosed mainly in children and young adults.

Type 1 diabetes affects approximately 1.5 million people in the United States.

The core issue of diabetes is an inability to control the level of glucose (sugar) in the blood.

Blood glucose levels are normally controlled by the hormone insulin, but the cells that make insulin (pancreatic beta cells) are destroyed by the immune systems of people with diabetes.

A lifetime of untreated diabetes can result in severe, debilitating consequences including kidney failure, adult blindness, nerve damage and blood vessel damage, the latter of which might lead to limb amputations, heart attack and stroke.

As a result of these complications, diabetes sufferers have an average life expectancy 10 years less than non-diabetic people;

Transplantation of pancreatic islets

Currently, the only treatment option for the many diabetes sufferers is a daily injection of insulin. Unfortunately, this treatment is unable to prevent the occurrence of complications in the majority of diabetics. This sad reality has driven scientists to find alternate strategies that will cure diabetes.

Figure 1: Fluorescent micrograph showing the components of a human islet in the normal human pancreas. Colors indicate both the presence of the major islet hormones and the arrangement of principle cell types that express those hormones. Red, insulin hormone within beta cells; Blue, somatostatin hormone within delta cells; Green, glucagon hormone within alpha cells. Image by author.

One exciting development has been the idea of transplanting new insulin-producing pancreatic beta cells taken from deceased human donors into living patients with diabetes. This treatment was first successfully pioneered by a medical team in Edmonton, Canada in the late 1990s.2 The Edmonton team transplanted people with pancreatic islets, the tissue that contains the insulin-producing beta cells. Since then, many hospitals around the world have established the transplant treatment as part of their protocols for addressing diabetes.3 However, it did not take long before scientists realized that transplanting pancreatic beta cells from human organ donors would never be able to successfully treat every patient.

Transplantation of insulin-producing beta cells, or islets, has been proposed as a potential treatment for Type 1 diabetes.

It quickly became apparent that, for a person to be cured of diabetes, it was necessary to provide each individual recipient with the equivalent of ‘two or more persons’ worth of pancreatic islets.3 This is in contrast to the fact that we can survive quite well with as little as a third of our own islets. The requirement for high numbers of islets is attributed to the rapid destruction and death of the islets following transplantation owing to the activation of an aggressive immune response against the newly transplanted tissue. Additionally, it is believed that transplanted islets are quite sensitive to their new environment, resulting in the death of many islets during the adjustment period.

Apart from the issues surrounding islet survival there is an additional problem; simply put, there are not enough islets available.

There are 1.5 million Type 1 diabetics in the US.

The number of suitable islet donors in the US is less than 5000 per year.

If each diabetes patient requires islets from two donors, we could transplant 2,500 diabetics each year. This amounts to less than 1% percent of the number of people who could benefit from such a therapy!

Solving the problem of supply

Although, conceptually, it seems easy to cure diabetes by transplanting new islets, it has been far more difficult in practice. The primary hurdle is finding a large enough supply of human islets for transplantation into all diabetes patients who could potentially benefit from this treatment. The limited supply of suitable organs and tissues plagues all transplant therapies. Currently in the US, the average wait time for a kidney from a deceased human donor is more than four years. The supply of islets and other organs from deceased human donors will never be sufficient to supply this need.

The current supply of human islets is not sufficient to treat all diabetes patients who could benefit.

In the case of islet transplantation one alternative is to take islets from living donors; however, this procedure has the risk of causing diabetes in the donor.

Another possibility is to use fetal tissue to grow new islets, but currently this is not possible because of technical limitations, as well as the ethical considerations pertaining to the use of human embryos.

The issue of supply has led many researchers to discuss whether we could transplant islets from other animals into humans (xenotransplantation).

Figure 2: Piglets that have been made to express new genes to aid human transplantation look much like regular pigs - except now they express new features at the molecular level. Image courtesy of Professor Peter Cowan, Immunology Research Centre, St Vincent’s Hospital Melbourne, Australia.

Pig islets are viewed by medical researchers as reasonable substitutes for human islets, owing to both physiological and practical considerations.

Although many different animal sources have been proposed, porcine (pig) islets seem to be the most popular choice for two reasons:

Physiological reasons: The blood levels of glucose in pigs and humans are similar and pig insulin works well in humans (pig insulin has been used for diabetes treatment).

Practical reasons: Knowledge pertaining to the commercial rearing and breeding of pigs for food could be used to develop facilities for large-scale preparation of pig islets.

The development of islet xenotransplantation

At this time, the use of pig islets for human transplantation is neither routine nor broadly practiced; however, a number of scientific studies have been conducted to test the feasibility of this idea.4

The first scientific attempt to transplant pig islets was conducted in 1994 by a team from the Karolinska Institute, Stockholm.5 The team transplanted pig islets into ten human patients who had diabetes and, in the process, demonstrated that transplanted islets made c-peptide, a by-product indicating insulin production, for up to 400 days. Although this study did not cure the patients, it showed for the first time that pig islets can survive and function in the human body.

Researchers have been studying how to increase the length of time that pig islets can survive in the human body to produce therapeutic benefits.

In 1996 a team from the University of Toronto, Canada, reported that they were able to cure diabetes in monkeys that were transplanted with pig islets microencapsulated in a special gel called alginate.6 The idea was that alginate would form a protective barrier around the islets, effectively protecting them from the immune system attack, which it did for up to 800 days in the study monkeys. This result was exciting as it showed that pig islets could cure diabetes without using immunosuppression.

In 2005 a team from Hospital Infantil de México, Mexico, placed pig islets in a specially designed protective metal device and transplanted this under the skin of young human patients with diabetes.7 This was controversial for many reasons and the reader is encouraged to read the editorial comment by Dr. Megan Sykes; however, the study did demonstrate, for the purposes of this discussion, that pig islets can be placed in the human body for potential medical benefit.8

In more recent years a scientific team from Auckland, New Zealand, has tested whether pig islets encapsulated in alginate (as in the 1996 study, above) could cure diabetes in people without requiring immunosuppression.4 So far no one has been cured, but studies are ongoing.

Xenotransplantation is also showing promising results in treating other human diseases, such as Parkinson’s disease.

Xenotransplantation for Parkinson’s disease

The idea of using pig organs and tissue in humans is not limited to curing Type 1 diabetes. Parkinson’s disease is a progressive degenerative disorder of the central nervous system in which specialized brain cells—called dopamine-generating cells—die, resulting in a range of symptoms affecting movement and motor coordination. Transplantation of pig neurons into the human brain has been attempted as a possible therapy to treat Parkinson’s disease. In a scientific trial in the 1990’s, 12 human patients with Parkinson’s disease were transplanted with pig neuronal cells.9 The study found that transplant recipients showed some improvement in their disease-related symptoms, indicating that transplanting pig neurons could be a novel cure. A more recent study in monkeys with a Parkinson-like disease showed that transplanted pig neuronal cells could significantly improve features of the disease for up to two years.10 These studies are still ongoing but demonstrate the potential to find new cures for human diseases using xenotransplantation strategies and technology.

Figure 3: Pancreatic beta cells (Red; Insulin hormone) are being invaded by immune cells (Green; T lymphocytes). Image from the pancreas of the non-obese-diabetic (NOD) mouse - an animal model used in medical research to study T1D. Image by author.

Transplant recipients require long-term immunosuppressant treatments, which come with their own set of potential risks and benefits.

Genetic engineering: suppressing the need for immunosuppression

Pigs may provide an excellent source of organs and tissues for the treatment of diseases like Type 1 diabetes and Parkinson’s. However, such approaches would still require addressing the problem of immune rejection of the organs and tissues following transplantation. The current strategy in most transplant situations is to suppress the recipient’s immune system with powerful inhibitory drugs known as immunosuppressants. Unfortunately, these drugs are not totally effective in preventing the immune attack on transplanted pig islets in people with diabetes. More importantly, the use of immunosuppression can be considered ethically unacceptable in some cases because of the potential for toxic side effects, such as increased risk of infections and cancer. Further, long-term use of immunosuppressants may cause developmental problems in children. Given the fact that transplant recipients must take such drugs for the duration of their lives, and that most Type 1 diabetics are children and young adults, these are important considerations.

This dilemma has again led to a search for new answers. One option is to encapsulate the islets in protective gels or devices to protect them from immune system attack. Another potential solution is to genetically engineer the pig tissues to be resistant to immune attack by artificially adding a gene to the tissue so it expresses a new characteristic or feature. The technique to generate genetically engineered pigs is called “somatic cell nuclear transfer.”

Genetic engineering could be used to produce “super islets” that cannot be destroyed by immune response factors.

As one example, a genetic engineering approach for diabetes might involve producing a “super” islet that cannot be destroyed. This idea is supported by research showing that normal cells in our bodies can protect themselves from dying, or being killed by the immune system, by making specialized protective proteins. It is suggested that if we genetically engineer islets to express these proteins, they might survive in the absence of any other treatment.11 In 2009 a group from Neustadt, Germany genetically engineered pigs so their cells all expressed one particular death-defying protein known as TNFAIP3.12 In experiments it was shown that cells from these engineered pigs were resistant to being killed by immune factors. With this technology, organs and tissues (like islets) could be taken from these pigs and be used for xenotransplantation.

Conclusion

There are still many important issues that need to be addressed before pig organs and tissues can be used in humans to treat diseases. One basic issue is to decide whether it is ethically acceptable to use animals as a source of “parts” for humans. The reader is directed to the xenotransplantation international consensus statement for further reading, which provides an ethical framework for clinical trials testing animal tissues in humans.13 If it is agreed that xenotransplantation is acceptable, the use of pigs may be more justifiable than non-human primates for the reason that pigs are currently utilized as a food source. Other issues are more technical but no less important. For instance, there has been a vigorous debate as to whether the use of pig tissues may expose the human population to dangerous new viruses. While extensive studies have found no evidence to support the existence of such viral transmission, this example illustrates the complexity of using new technologies to cure human diseases such as Type 1 diabetes.

Shane T. Grey, Associate Professor in Medicine and ARC Future Fellow and Honorary National Health and Medical Research Council (NHMRC) Senior Research Fellow, is a medical researcher based at the Garvan Institute in Sydney. Shane received his PhD training in immunology at Monash University, Australia and post-doctoral training as a transplant immunologist at Harvard Medical School. Grey became involved in Type 1 diabetes research though the JDRF (formerly the Juvenile Diabetes Research Foundation) Islet Transplant Center at Harvard in the late 1990’s. He later received a JDRF Career Development Award to establish a research program aiming to understand how beta cells die. Shane is currently involved in both basic and clinical studies to improve the success of islet transplantation and basic research into the mechanisms of graft rejection and Type 1 diabetes. Shane is the head of a research team at the Garvan, a co-investigator in Australia’s first clinical islet transplant program, and Director of a national research program funded by JDRF and the NHMRC which aims to work out why beta cells die after transplantation.

Xenotransplantation for the Treatment of Type 1 Diabetes

learnmore links

International Xenotransplantation Association

A section of The Transplantation Society, the International Xenotransplantation Society aims to foster the science of xenotransplantation through promotion of ethical clinical and pre-clinical research, productive discourse, and collaboration. The IXA also works to guide the development of scientifically sound public policy that is responsive to new developments in the field.
http://www.tts.org/index.php?option=com_content&view=article&id=51&Itemid=35

Xenotransplantation in pediatrics

Dr. William E. Beschorner provides a comprehensive overview of xenotransplantation, including background, information on xenozoonoses (infectious agents passed from donor animals to human patients), a history of clinical xenotransplantation, and the future of the technology.
http://emedicine.medscape.com/article/1014080-overview

FDA guidance for industry: public health issues posed by the use of non-human primate xenografts in humans

The Islet Foundation

The Islet Foundation (TIF) focuses its resources and efforts on supporting research into islet replacement without immunosuppression as a means to cute insulin-dependent diabetes. TIF aims to provide information on the most promising research to funding organizations and key investors, including the National Institutes of Health (NIH), the American Diabetes Association (ADA), the Juvenile Diabetes Foundation (JDF), and the US Food and Drug Administration (FDA). Current educational resources include reports from international xenotransplantation workshops, CDC & FDA reports and testimony before NIH panels, as well as editorials and scientific papers on the potential risks and benefits associated with xenotransplantation.
http://islet.org/index.htm

getinvolved links

Clinical Trials

The National Institutes of Health (NIH) provides a detailed database of recent and ongoing clinical trials involving human participants, including both publicly and privately funded studies. Search for “diabetes islets” to see studies relevant to diabetes and islet transplantation, including study status, summary, and sponsors/collaborators.
http://www.clinicaltrials.gov/

American Diabetes Association

The American Diabetes Association (ADA) plays a leading role in efforts to increase funding to prevent, treat, and cure diabetes; improve access to health care and eliminate discrimination against people with diabetes at school, work and elsewhere in their lives. Visit the ADA website to learn more about how you can support these efforts and advocate for chance in Washington, DC, state capitols, and the court system.
http://www.diabetes.org/

Campaign for Responsible Transplantation

The Campaign for Responsible Transplantation (CRT) is a non-profit organization that believes xenotransplantation poses a significant risk to human health, in addition to environmental, economic, ethical and legal problems. CRT’s international coalition includes more than 90 public interest groups.
http://www.crt-online.org/

educatorresources

Teaching Resources from the Northwest Association for Biomedical Research (NWABR)

The Northwest Association for Biomedical Research (NWABR) strengthens public trust in research through education and dialogue. Its diverse membership spans academic, industry, non-profit research institutes, health care, and voluntary health organizations. Through membership and extensive education programs, it fosters a shared commitment to the ethical conduct of research and ensures the vitality of the life sciences community.

Animals in Research
Through this curriculum, students are introduced to the complex topic of Animal Research using structured discussion, stakeholder activities, case studies, and the ethical frameworks used by those in support of, and in opposition to, this work. One of the goals of the curriculum is for students to support their own position on this issue through well-reasoned, fact-driven justifications in a classroom atmosphere of respectful dialogue.
http://www.nwabr.org/curriculum/animals-researchFor the Greater Good
The “For the Greater Good” series is composed of five featured articles. Each article portrays one author’s personal stories of people and animals whose lives have been improved or saved by medical breakthroughs made possible by animal research. The Curriculum Guide includes a 5-lesson unit outlining the use of models in both science and ethics, and provides resources for exploring the use of animals in research.
http://www.nwabr.org/curriculum/greater-goodThe Science and Ethics of Humans in Research
This curriculum unit introduces students to how research with humans is conducted, the rules and regulations involved, and the bioethical principles that guide scientists when involving humans in research. Lesson strategies and bioethical discussions engage students in science content and promote an understanding of the role of science in society.
http://www.nwabr.org/sites/default/files/Science_Ethics_of_Humans_in_Research9.12.pdf

Xenotransplantation: Using animal organs to save human lives

The NIH “Snapshots of Science and Medicine” website includes a variety of resources for middle and high school classrooms, including news articles about xenotransplantation, highlights of scientists conducting xenotransplantation research, the social impacts of this technology, and a teachers’ guide to facilitate student learning and comprehension.
http://science.education.nih.gov/newsnapshots/TOC_Xeno/toc_xeno.html